The HPA Axis and Hypoglycemia: A Vicious Cycle
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The HPA Axis and Hypoglycemia: A Vicious Cycle
Last week I wrote about reactive hypoglycemia, a form of blood sugar dysregulation in which blood sugar plummets after a meal, primarily in response to the overconsumption of refined carbohydrates and sugars. However, these foods are not the only cause. One other primary cause of hypoglycemia is dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. This week we’ll continue talking about blood sugar and go into more detail about the relationship between the HPA axis and hypoglycemia.
Normally the adrenal glands kick into action in response to low blood sugar, as in the case of a skipped meal. When we miss a meal and we become hypoglycemic, the adrenal glands release stress hormones like cortisol that raise blood sugar. In this role, the adrenals can be thought of as an “emergency backup.” They also play a central role in the “fight or flight” sympathetic nervous system response. The adrenal glands are part of a larger picture neuroendocrine system known as the HPA axis, which we will explore in more detail shortly.
Over time, downregulation of the HPA axis can lead to a vicious cycle of blood sugar imbalance. Long-term recurrence of hypoglycemic episodes puts a lot of strain on the adrenal glands, which over time become unable to raise blood sugar through the release of cortisol, a primary stress hormone. This can become a vicious cycle in which the adrenal glands are unable to raise blood sugar, resulting in hypoglycemic symptoms such as dizziness, shakiness, perspiration and a short temper, which is commonly referred to as being “hangry.”
To learn about the physiology that underlies this phenomenon, commonly referred to as “adrenal fatigue” or “adrenal insufficiency,” keep reading! I’ll cover how to support the adrenal glands and rebalance the HPA axis in order to get out of this vicious cycle!
The HPA axis and its role in the stress response
The HPA axis is a neuroendocrine system that leaps into action in response to perceived stress. The hypothalamus initiates the stress response cascade by releasing corticotropin-releasing hormone (CRH). CRH binds to receptors on the anterior pituitary gland, which in turn stimulates the pituitary to release adrenocorticotropic hormone (ACTH). Receptors on the zona fasciculata region of the adrenal cortex bind ACTH and stimulate the adrenal release of cortisol into the bloodstream.
The hypothalamus monitors blood concentrations of cortisol, and when levels reach an adequate level the hypothalmus concludes that the stress has been controlled and dealt with. Elevated blood cortisol levels signal the hypothalamus to stop releasing CRH through a negative feedback loop. In response, the pituitary stops releasing ACTH, which in turn stops stimulating the adrenal release of cortisol and homeostasis is achieved.
Not just the adrenal glands are implicated
The adrenal glands themselves are sometimes viewed as the culprit and we hear about “adrenal fatigue” as an explanation for the body’s inability to release sufficient cortisol to raise blood sugar. Although the adrenals are an important component of the body’s stress response, we must also consider the hypothalamus and pituitary to understand the bigger picture. Keep reading to learn how these “upstream” glands that govern adrenal function factor into the larger picture.
What does the body consider to be stressful?
Before we get to the details of the HPA axis, let’s talk about stress, since stress is a primary activator of the HPA axis.
Stress can come from many sources. From an evolutionary point of view, stressors were generally situations that could be life threatening, such as the presence of a lethal predator that one must either incapacitate or run away from, hence the term “fight or flight.” Other stressors include situations in which a child or another member of the tribe is in danger, as in the case of a child falling into a rushing river. The stress response kicks into action to give us a temporary burst of superhuman strength and energy to outrun the bear or rescue the helpless child from the raging rapids.
Today, we have largely removed ourselves from the food chain and live pretty safe lives in comparison to much of our evolutionary history. However, we deal with different sources of stress today. Stress today tends to be more chronic. We’ll review a few common contemporary stressors here:
- Watching a suspenseful TV show or movie
- Job stress, such as an angry boss or an upset customer
- Fear about public speaking at an upcoming meeting
- Being involved in a car accident or a near-collision
- Excessive exercise, especially sustained exercise like marathon running
- Hypoglycemia – this is a big one that we’ll return to shortly!
Although some of these stressors may sound relatively trivial, they stimulate the same physiological stress response in the body as being chased by a bear. Some other, more serious forms of chronic stress can result from:
- Sexual assault and other forms of trauma
- PTSD, as in the case of war veterans
- Being a caregiver for a chronically ill family member
- Emotional stress resulting from depression or abuse
The effects of chronic stress
In contrast to occasional acute stress such as a bear that we must outrun to survive, much of today’s stress is chronic. Chronic stress, such as an overbearing or unreasonable boss that stresses us out at the office all day long results in frequent stimulation of the HPA axis and elevated cortisol levels. Over time, the stress response becomes blunted as the adrenal glands become less responsive to ACTH. As a result, cortisol levels decline, which we see in our office when performing DUTCH cortisol urine testing.
We like the DUTCH test because it assesses levels of cortisol four times over the course of the day. Normally, cortisol levels are highest in the morning as this hormone helps to stimulate us to wake up. Cortisol levels then decline over the course of the day and typically reach their lowest levels in the evening and night when we become tired and go back to sleep. However, what we see in our clinic with adrenal insufficiency is consistently low levels of cortisol over the course of the day.
The difference between chronic and acute stress
A helpful analogy to understand the difference between chronic and acute stress and how the HPA axis is intended to function is to observe a wild animal such as a deer. Picture a deer in a meadow, peacefully munching on grass. Suddenly, a wolf appears on the horizon and begins running toward the deer at full speed, hoping to turn Bambi into a nice lunch for himself. In a split second, the deer’s HPA axis shifts the nervous system into “fight or flight” and its adrenal glands secrete cortisol into the bloodstream.
Bambi takes off at full speed, and thankfully is able to outrun and elude the wolf, which gives up and goes after other, easier prey. After determining that the threat has passed, what does the deer do? He settles down in the shade and takes a nap. This period of rest allows the HPA axis to reset and recharge. This component of rest and rejuvenation is crucial, and is much different than what happens in cases of chronic stress.
Chronic stress paints a much different picture. Picture Bill, a sales associate who works in a busy office. A stressful morning meeting in which Bill’s boss grills him for numbers that aren’t up to par initiates a stress response and sends cortisol into Bill’s bloodstream. After the meeting, Bill grabs a cup of coffee to give him an energy boost. The coffee stimulates the release of more cortisol, and then Bill skips lunch to catch up on paperwork, which results in even more stress and cortisol release. Then, Bill spends his afternoon “putting out fires” and finishes out the rest of his day just as stressed as he started.
Unlike the deer in the previous example, Bill doesn’t get a chance to rest and instead stays in “fight of flight” mode all day. Over a period of several weeks or months, Bill’s ability to respond appropriately to stress is compromised, resulting in downregulation of the HPA axis. With this understanding of the difference between acute and chronic stress in mind, we’ll talk next about the vicious cycle of HPA downregulation and hypoglycemia.
The hypoglycemia connection
As I alluded to earlier, hypoglycemia can be both a cause of, and result of HPA axis dysregulation. Hypoglycemia that results from frequently skipping meals puts strain on the adrenal glands, which respond by secreting cortisol. Elevated cortisol levels stimulate gluconeogenesis, a process by which glucose is synthesized from pyruvate (1). Gluconeogenesis primarily takes place in the liver and kidneys and is one primary way the body is able to raise blood sugar levels.
But when the HPA axis becomes downregulated, the adrenal glands become resistant to the stimulatory effects off ACTH. Consequently, they do not secrete as much cortisol. This imbalance is commonly referred to “adrenal fatigue” or “adrenal insufficiency,” but as I described earlier the problem involves the whole HPA axis and not just the adrenals.
Whatever terminology is used to describe this phenomenon, the end result is that the adrenal glands no longer secrete adequate amounts of cortisol to raise blood sugar and the ability to resolve hypoglycemia by activating gluconeogenesis is compromised.
Testing for HPA dysregulation
An important first step in treating hypoglycemia that is related HPA dysregulation is establishing a baseline cortisol profile through a DUTCH adrenal dried urine test. This is our preferred test because it evaluates cortisol levels four times over the course of a 24 hour period. The DUTCH test is preferable to single collection cortisol tests that only measure total cortisol for a 24 hour period because total cortisol for the day doesn’t provide as clear of a picture. For example, low levels of cortisol throughout much of the day could be hidden by a cortisol spike that pushes total cortisol for the period into normal, or even elevated ranges.
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HPA downregulation vs upregulation
The HPA axis can either be down- or upregulated. Different treatment options are indicated depending on which direction the HPA axis is skewed. When the HPA axis is downregulated, we see symptoms like low blood pressure and dizziness upon standing, in particular. When transitioning from sitting to standing, the body must raise blood blood pressure to combat the effects of gravity. When it is unable to do so, we feel dizzy upon standing because not enough blood is reaching the brain.
Dizziness upon standing is referred to as orthostatic hypotension, which your functional medicine practitioner can test for by taking your blood pressure while sitting and then taking it again immediately upon standing. Orthostatic hypotension is commonly caused by HPA axis downregulation, when the adrenal glands are not able to secrete sufficient cortisol and adrenaline to raise blood pressure quickly enough.
Another common symptom of HPA downregulation is frequent urination, or polyuria, which results from depressed aldosterone levels. As the HPA axis becomes downregulated and the adrenals become fatigued, they produce less aldosterone. Because aldosterone regulates the excretion of salt, functionally low aldosterone can result in the overexcretion of salt. This is one reason why many people with a downregulated HPA axis crave salt. Because water follows salt, polyuria results, followed in turn by low blood pressure and dizziness upon standing.
Not surprisingly, many people with adrenal insufficiency crave salt. Increasing salt intake can be helpful for those with a downregulated HPA axis. In contrast, someone with upregulated HPA axis may benefit from decreasing salt intake, especially in the presence of high blood pressure. Salt can also be stimulatory to the adrenals and raise blood pressure, but other factors like potassium intake have more significant impact on blood pressure for some people than salt. Salt sensitivity is a possibility for high blood pressure but it’s not the only cause. In cases of either HPA upregulation or downregulation, a good sea salt like pink Himalayan salt is a better choice than table salt because it also contains other necessary trace minerals, in addition to sodium.
Treatments for HPA dysregulation
As with most (if not all) health conditions, a proper diet provides the crucial foundation for health. We stress the importance of a suitable diet with patients who are dealing with HPA dysregulation. If you suspect that your adrenal function may be compromised and leading to hypoglyemia, a good first step is to make sure your diet is supporting stable blood sugar.
Here are some key dietary components:
- Eat well balanced meals
- Include adequate protein and plenty of healthy fats with each meal
- Avoid sugars and excessive carbohydrates, especially refined carbohydrates
- Eat regularly and don’t skip meals
- It may be necessary at first to eat every 2-3 hours until blood sugar stabilizes
- Include protein and healthy fats with each snack
- Eat breakfast within one hour of waking
- Avoid caffeine
- Caffeine stimulates the adrenal glands to release cortisol, which provides an energy boost
- It’s important to avoid caffeine to give adrenals a chance to rest and recover
- Drink plenty of water
- Especially if you’ve relied on coffee, rehydrating is important, as caffeine acts as a diuretic
- Include sources of minerals and electrolytes like coconut water, spring water and mineral water
Other treatment options
In addition to a proper diet, these recommendations can help rebalance the HPA axis:
- Practice mindfulness and relaxation techniques
- Meditation, qi gong, yoga and other practices help bring the body out of the “fight of flight” sympathetic nervous system that drives cortisol and stresses the adrenals (2)
- Consume adaptogenic herbs, either in supplement form or as a tea
- Ashwaganda is a calmative adaptogen that supports adrenal health and can be used at night to help relax and sleep (3)
- Tulsi basil, aka Holy basil has been used for centuries and has also shown to modulate stress in research (4)
- Rhodiola is a more energizing adaptogen that can be helpful to overcome fatigue (5)
- Consume more magnesium
- Magnesium is a commonly deficient nutrient that aides in relaxation
- Epsom salt baths are both relaxing and a good way to get more magnesium into the body
- Take magnesium supplements at least 30 minutes before or 90 minutes after a meal
- Use lavender essential oil
- Lavender has been shown to decrease cortisol (6)
- Put a few drops on your pillow at night
- Try 10 drops of lavender oil in your Epsom salt bath
- Avoid excessive exercise and space out your workouts
- Avoid sustained exercise over long periods of time
- Moderate exercise can improve ACTH sensitivity, whereas prolonged exercise like marathon running is a stress to the body (7)
- Vitamin C
- This nutrient is highly concentrated in the adrenal glands and is quickly used up in stressful situations
- A study on cardiac patients preparing to undergo surgery showed significantly decreased cortisol when pretreated with Vitamin C (8)
- Pantothenic acid / Vitamin B5
- A rat study showed that Vitamin B5 increased adrenal sensitivity to ACTH (9)
Managing stress and supporting the HPA axis are important components of keeping blood sugar stable. Because hypoglycemia and HPA axis dysregulation can work together to create a vicious cycle, it’s important to work with a functional medicine practitioner who can evaluate whether these issues underlie symptoms you are experiencing.
In addition, chronic stress has been shown to increase vulnerability to many physical and psychiatric health conditions including clinical depression (10), acquired immunodeficiency syndrome (AIDS) (11) and coronary heart disease (12). For these reasons, and others not listed here, managing stress and maintaining a healthy stress response appears to be critical to many areas of health.
Because of the interrelated nature of hypoglycemia and HPA axis dysregulation and research showing the many negative health outcomes associated with chronic stress, we think it’s important to “stress” stress management and adrenal health!
- Khani, Samina, and John A. Tayek. “Cortisol Increases Gluconeogenesis in Humans: Its Role in the Metabolic Syndrome.” Clinical Science 101.6 (2001): 739. Web.
- Bergen-Cico, Dessa, Kyle Possemato, and Wilfred Pigeon. “Reductions in Cortisol Associated With Primary Care Brief Mindfulness Program for Veterans With PTSD.” Medical Care 52 (2014): n. pag. Web.
- Chandrasekhar, K., Jyoti Kapoor, and Sridhar Anishetty. “A Prospective, Randomized Double-blind, Placebo-controlled Study of Safety and Efficacy of a High-concentration Full-spectrum Extract of Ashwagandha Root in Reducing Stress and Anxiety in Adults.” Indian Journal of Psychological Medicine 34.3 (2012): 255. Web.
- Saxena, Ram Chandra, Rakesh Singh, Parveen Kumar, Mahendra P. Singh Negi, Vinod S. Saxena, Periasamy Geetharani, Joseph Joshua Allan, and Kudiganti Venkateshwarlu. “Efficacy of an Extract OfOcimum Tenuiflorum(OciBest) in the Management of General Stress: A Double-Blind, Placebo-Controlled Study.” Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1-7. Web.
- Olsson, Emg, B. Von SchÃ©ele, and Ag Panossian. “A Randomised, Double-blind, Placebo Controlled, Parallel Group Study of the Standardised Extract SHR-5 of the Roots of Rhodiola Rosea in the Treatment of Subjects with Stress-related Fatigue.” Planta Medica 75.09 (2009): n. pag. Web.
- Heydari, Alemeh, Seyedabedin Hosseini, Mohammadali Vakili, Shahram Moghadam, and Sadeghali Tazyky. “Effect of Lavender Essence Inhalation on the Level of Anxiety and Blood Cortisol in Candidates for Open-heart Surgery.” Iranian Journal of Nursing and Midwifery Research 21.4 (2016): 397. Web.
- Roelfsema, Ferdinand, Rebecca J. Yang, Thomas P. Olson, Michael J. Joyner, Paul Y. Takahashi, and Johannes D. Veldhuis. “Enhanced Coupling within Gonadotropic and Adrenocorticotropic Axes by Moderate Exercise in Healthy Men.” The Journal of Clinical Endocrinology & Metabolism (2017): n. pag. Web.
- Das, Deepanwita, Chaitali Sen, and Anupam Goswami. “Effect of Vitamin C on Adrenal Suppression by Etomidate Induction in Patients Undergoing Cardiac Surgery: A Randomized Controlled Trial.” Annals of Cardiac Anaesthesia 19.3 (2016): 410. Web.
- Jaroenporn, Sukanya, Tatsuya Yamamoto, Asuka Itabashi, Katsuhiro Nakamura, Isao Azumano, Gen Watanabe, and Kazuyoshi Taya. “Effects of Pantothenic Acid Supplementation on Adrenal Steroid Secretion from Male Rats.” Biological & Pharmaceutical Bulletin 31.6 (2008): 1205-208. Web.
- Gold, P. W., and G. P. Chrousos. “Organization of the Stress System and Its Dysregulation in Melancholic and Atypical Depression: High vs Low CRH/NE States.” Molecular Psychiatry 7.3 (2002): 254-75. Web.
- Sheridan, J. F., C. Dobbs, D. Brown, and B. Zwilling. “Psychoneuroimmunology: Stress Effects on Pathogenesis and Immunity during Infection.” Clinical Microbiology Reviews7.2 (1994): 200-12. Web.
- Rozanski, A., J. A. Blumenthal, and J. Kaplan. “Impact of Psychological Factors on the Pathogenesis of Cardiovascular Disease and Implications for Therapy.” Circulation99.16 (1999): 2192-217. Web.
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